Non–small cell lung cancer (SCLC) patients with specific epidermal growth factor receptor (EGFR) gene mutations are known to show a great response to initial treatment with EGFR tyrosine kinase inhibitors (EGFR-TKIs).1 However, in most cases, the tumor develops resistance to the initial EGFR-TKI after ~3 to 25 months of treatment.2,3 Several mechanisms have been reported to underlie the development of resistance, with the most frequent being an additional T790M mutation of exon 20 in EGFR. The other major mechanisms that have been reported include MET amplification, HER2 amplification, and histologic transformation.4 Osimertinib (a third-generation EGFR-TKI) has shown dramatic effects in patients with active EGFR mutations who showed resistance to EGFR-TKIs due to a resistance mutation (exon 20, T790M).5 Thus, it is important to understand the mechanism of resistance before selecting the treatment regimen. The current guideline recommends that the cell-free DNA testing using blood be performed if a biopsy is not possible or not recommended.6 Tissue testing is recommended when it is feasible. The rebiopsy of the tissue to explore the resistance mechanism has an advantage of enabling a histologic reevaluation for detecting histologic change as a resistance mechanism.
The patient was a 64-year-old man who had been diagnosed with pulmonary adenocarcinoma of the middle lobe (c-T2aN0M0, c-stage IB). The patient underwent middle lobectomy with lymph node dissection, which was performed with curative intent (Figs. 1A, B). Unfortunately, the surgical pathology revealed multiple mediastinal node metastases (station 2R: right superior paratracheal, station 4R: right inferior paratracheal, station 7: subcarinal, and subsegmental lymph node). EGFR mutation testing revealed an exon 19 deletion and the patient agreed to enroll in a clinical trial of adjuvant chemotherapy using EGFR-TKI (Gefitinib: 250 mg/d) (Clinical Trial Registry Number: UMIN000006252).
Twenty-one months later, while receiving adjuvant treatment, station 2R became enlarged (Fig. 1C). Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) with a dedicated 22-G needle (NA-201SX-4022; Olympus, Tokyo, Japan) was performed and the histologic diagnosis was transformation to SCLC. We did not detect an exon 20 T790M mutation; however, the original EGFR exon 19 deletion mutation was maintained (Fig. 1D). A positron emission tomography scan exhibited an abnormal fluorodeoxyglucose uptake in the right neck and the right supraclavicular lymph nodes. Because of the SCLC histology, the patient received combination chemotherapy consisting of cisplatin (60 mg/m2 on day 1) and irinotecan (60 mg/m2 on days 1, 8, and 15) every 4 weeks. After receiving 4 cycles of the chemotherapy, it was judged that the patient showed a complete response (according to the RECIST criteria7).
At ~6 months after chemotherapy for SCLC, station 7 became enlarged (Fig. 1E) and a rebiopsy with EBUS-TBNA revealed the recurrence of adenocarcinoma with an EGFR exon 19 deletion without a T790M exon 20 mutation (Fig. 1F). A blood-based sampling of cfDNA was not performed. The patient was treated with afatinib; however, he developed multiple pulmonary and brain metastases and died 42 months after surgery. Autopsy was declined by the family.
The importance of performing repeat tumor biopsies in cases involving patients with acquired resistance to initial molecular targeted therapy has increased due to the development of novel therapeutic agents that overcome resistance, which develops via specific mechanisms. A test to detect EGFR exon 20 T790M mutations through blood-based sampling of cfDNA was recently introduced in the clinical setting and there is some controversy with regard to whether or not patients should be evaluated by a repeat biopsy or blood-based testing. The current National Comprehensive Cancer Network guidelines recommend the following: (1) a plasma biopsy should be considered if a tissue biopsy is not feasible; and (2) tissue-based testing should be considered if a plasma test is negative for T790M mutations. The present case was treated following the current guideline, and obtaining tissue repeatedly was helpful for determining the presence of histologic transformation, as histologic transformation should be considered when a tumor shows resistance to the initial EGFR-TKI, and because an active EGFR mutation might mislead physicians to select an inappropriate treatment regimen even though histologic transformation is detected.
Several mechanisms of acquired resistance have been identified, the most frequently reported of which involves exon 20 T790M mutations; the frequency of histologic transformation to SCLC is reported to be 3% to 14%.4,8 The transformation of adenocarcinoma to SCLC is associated with a minimal response to EGFR-TKIs.9
A rebiopsy should always be considered when a patient shows resistance to the initial EGFR-TKI; however, second and third biopsies are not always performed as smoothly as the first biopsy due to various technical difficulties. A bronchoscopic biopsy with ultrasound guidance is reported to be highly reliable (in terms of safety) and is usually applied to make a precise diagnosis, even for the rebiopsy.10 A previous report showed the success rate of EGFR mutation testing using samples obtained by EBUS-TBNA was very high. Therefore, EBUS-TBNA can be considered a favorable biopsy modality for biomarker testing including rebiopsy in patients with lung cancer. EBUS-TBNA has been proven useful for obtaining repeated samples.11
Based on the current evidence, conventional combination chemotherapy for SCLC should be selected for SCLC transformation. 9 Even for SCLC with transformation from other histologies, the response rate to standard platinum-based combination chemotherapy reached 83% which was not inferior to the treatment outcome for de novo SCLC (response rate of 70% to 90% for limited disease).12 However, even with a favorable response to standard chemotherapy for SCLC, the overall survival of SCLC transformed from adenocarcinoma was only 7.1 months which was inferior to that of de novo SCLC (14 to 20 mo for limited disease and 9 to 11 months for extensive disease).12
In conclusion, when a tumor shows resistance to EGFR-TKIs, it is necessary to understand the genetic alterations underlying the acquisition of resistance (ie, T790M mutations), as well as the histologic subtype, due to the possibility of SCLC transformation.
We thank Professor Yukio Nakatani and Dr Satoshi Ota (Department of Diagnostic Pathology, Chiba University graduate School of Medicine) who made the pathologic diagnosis.
1. Mitsudomi T, Morita S, Yatabe Y, et al. Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer
harbouring mutations of the epidermal growth factor receptor (WJTOG3405): an open label, randomised phase 3 trial. Lancet Oncol. 2010;11:121–128.
2. Pao W, Miller VA, Politi KA, et al. Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain. PLoS Med. 2005;2:e73.
3. Sequist LV, Yang JC, Yamamoto N, et al. Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J Clin Oncol. 2013;31:3327–3334.
4. Sequist LV, Waltman BA, Dias-Santagata D, et al. Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors. Sci Transl Med. 2011;3:75ra26.
5. Mok TS, Wu YL, Ahn MJ, et al. Osimertinib or platinum-pemetrexed in EGFR T790M-positive lung cancer
. N Engl J Med. 2017;376:629–640.
6. Wu YL, Sequist LV, Hu CP, et al. EGFR mutation detection in circulating cell-free DNA of lung adenocarcinoma patients: analysis of LUX-Lung 3 and 6. Br J Cancer. 2017;116:175–185.
7. Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45:228–247.
8. Yu HA, Arcila ME, Rekhtman N, et al. Analysis of tumor specimens at the time of acquired resistance to EGFR-TKI therapy in 155 patients with EGFR-mutant lung cancers. Clin Cancer Res. 2013;19:2240–2247.
9. Oser MG, Niederst MJ, Sequist LV, et al. Transformation from non-small-cell lung cancer
to small-cell lung cancer
: molecular drivers and cells of origin. Lancet Oncol. 2015;16:e165–e172.
10. Izumo T, Matsumoto Y, Chavez C, et al. Re-biopsy by endobronchial ultrasound procedures for mutation analysis of non-small cell lung cancer
after EGFR tyrosine kinase inhibitor treatment. BMC Pulm Med. 2016;16:106.
11. Nakajima T, Yasufuku K, Fujiwara T, et al. Recent advances in endobronchial ultrasound-guided transbronchial needle aspiration. Respir Investig. 2016;54:230–236.
12. Jiang SY, Zhao J, Wang MZ, et al. Small-cell lung cancer
transformation in patients with pulmonary adenocarcinoma: a case report and review of literature. Medicine (Baltimore). 2016;95:e2752.